American Industry and the U.S. Cardiovascular Clinical Research Enterprise

An Appropriate Analogy?

• clinical trials
• internationality
• National Institutes of Health

The report by Kim et al. (1) in this issue of the Journal documents the increasingly widespread phenomenon of the “offshoring” of clinical research—in this case, clinical trials conducted in foreign countries despite being funded by U.S. taxpayers, administered through grants and contracts from the National Heart, Lung, and Blood Institute (NHLBI), and intended to inform American practice decisions. This report is 1 of a number of recent reports that raise the question of whether American clinical research, like many other U.S. industries, has become so expensive and inefficient that it is no longer a viable competitive enterprise within our borders.

Clinical research provides the quantitative evidence that consumers, patients, health care providers, and payers need to weigh risks and benefits when making decisions about medical care. Unfortunately, there is a dearth of high-quality evidence to support such decision making. Even in cardiovascular medicine, which has one of the most substantial evidence bases among specialties, only a relatively paltry 15% of guideline recommendations are supported by findings from definitive randomized trials (2). The widening gap between our need for high-quality evidence and our capacity to produce it is increasingly manifest. The way to bridge this gap, however, is less obvious: should we attempt to improve U.S. performance in clinical research conduct, move research to regions that offer efficiencies and cost savings, or both?

When an intervention is evaluated outside the environment in which it will ultimately be used, the results achieved in practice may differ from those observed in trials. Recent U.S. Food and Drug Administration data show that when multiregional clinical trials are conducted, the magnitude of the treatment effect is often smaller for U.S. volunteers compared with participants randomized abroad (3). The reasons for this are not entirely clear, but genetics, practice patterns (including the use of concomitant medications and procedures), environment, culture (including diet), health care system structure, and the play of chance all likely contribute to the phenomenon.

We also note that clinical research creates attractive, high-paying jobs. Given the current U.S. economic climate, the realization that through National Institutes of Health (NIH) funding, American tax revenues are supporting the export of good jobs abroad may prove economically and politically unattractive.

Nevertheless, we strongly believe that the globalization of clinical research is a powerful social good (4) when it stems from a universal need for collaborative research that informs each country's practice and reflects the biology of relevant populations. But when research is offshored predominantly because the U.S. enterprise has become incapable of conducting it efficiently, we must focus our attention on fixing our own system.

The myriad problems besetting American clinical research are well documented. The system is slow and often fails to meet recruitment targets. It is more costly than other systems and suffers from poor quality, as evidenced by high rates of nonadherence to study protocols and treatments and trial withdrawal by study participants. Furthermore, there is no reliable indication that the American system produces data that are of higher quality or better managed than data collected outside of the United States. Unsurprisingly, investigators have become discouraged, and an exodus of talent has recently ensued (5).

When we consider that clinical research offers cardiovascular specialists the chance to lose money, make their practices less efficient, incur risks from regulatory infractions, and contend with reputational problems arising from involvement with industry, we should not be surprised at these trends. Only the intellectual excitement, challenge, and fun of answering critical questions while participating in advancing knowledge keep the investigator pool at its current level. From our experience leading an academic coordinating center for clinical trials, we note that although there are approximately 5,000 acute care hospitals in the United States, only about 5% consistently participate in trials, and 1% account for the vast majority of participant accrual (L. Berdan, personal communication, February 2011).

Although the many disincentives for participating in clinical research are plain, the causes underlying the inefficiencies of our most powerful academic medical centers, which receive the majority of NIH funding, are more obscure. While the National Cancer Institute has been evaluating this problem (6) and the NHLBI has initiated its own effort (Clinical Research United in Successful Enrollment) to address the issue, we believe the current situation is actually a predictable by-product of the evolution of modern American medical schools. When the NIH emerged as the primary funding engine of global basic biological research in the postwar era, schools of medicine focused on building capacity to respond to requirements imposed by this funding juggernaut. Concurrently, the profitability of industry-funded clinical research gave rise to a common assumption that private industry rather than government could pay for it. Equally important, the concepts of unbiased evidence generation and clinical effectiveness, as well as the daunting need for larger sample sizes to reliably detect modest treatment effects, had not yet emerged (7).

The result of this history is clear to anyone who makes rounds in our “best” academic medical centers. Little priority is afforded to clinical research, and faculty members who do participate in multicenter trials get little academic credit unless they lead those trials. Furthermore, “indirect” funding from the NIH is often diverted from infrastructure needed for clinical research and allocated to support discovery science infrastructure. Consequently, there is a prevailing notion among many academic medical centers that participation in multicenter collaborative investigations constitutes second-tier research.

As with all U.S. health care delivery systems, academic health and science systems are hard pressed to find efficiencies, and the clinical enterprise has little tolerance for slowing practice to accommodate prolonged consent processes or for deferring profitable procedures. Despite the widely touted tripartite mission of clinical care, research, and education, clinical investigators and study coordinators usually work without support from their hospital units and clinics; in fact, the relationship is often adversarial, because the clinical care enterprise regards research as impeding efficiency and thus threatening its profitability.

Several critical misconceptions underlie this systemic failure. Previously, the large profits produced by cardiovascular practices meant that the NIH could count on significant cost sharing for clinical research; consequently, NIH funding often fails to adequately reimburse costs. Presently, however, while the hospital-facility side of U.S. cardiovascular medicine is profitable, the physician–clinical delivery side breaks even at best. And because salaries are flat or declining, there are no excess monies for cost sharing.

Another canard is the idea that a portfolio including industry-sponsored research can ameliorate these funding gaps. However, industry understandably funds trials most likely to provide a return on investment and thus is likely to explore questions that differ from those posed by trials designed to investigate issues relevant to the public health. Additionally, industry-funded trials, which frequently involve contract research organizations, have largely shifted away from academic centers and toward the private setting to avoid challenges in dealing with the complexities of the former.

Finally, there is a widely held view among leading academic centers that clinical research should not need institutional support. Before the modern clinical trials era, when clinical research was typically a small-shop enterprise or even a hobby for interested clinicians, this view might have been justifiable. However, increasingly sophisticated trial methodologies, along with a regulatory regime requiring extensive infrastructure and imposing substantial penalties for failure to ensure quality in data acquisition, data analysis, or protection of research participants, have made clinical research a professional activity and no longer a pastime for hobbyists.

Recognizing that this problem is endemic across specialties and disease areas, former NIH director Elias Zerhouni wisely created the Clinical and Translational Science Awards to provide a home for clinical and translational researchers within academic health and science systems (8). But despite a commitment of $500 million per year, as well as considerable effort and significant progress in other areas of translation (9,10), there is as yet no evidence that clinical research has become more efficient. We hope the decision to place the Clinical and Translational Science Awards under the new National Center to Advance Translational Science signals an intent to hold academic health and science systems accountable for prioritizing the conduct of efficient clinical trials that generate the medical evidence American providers, patients, and policy makers need to make rational health care decisions.

The NHLBI has an opportunity to lead the way toward a future in which the U.S. clinical research system, instead of becoming an obstacle to be circumvented, participates fully in global efforts to produce relevant, high-quality evidence to guide cardiovascular clinical practice. We suggest the following measures:

• 1. Separate payment for the proper recruitment, consent, and enrollment of research participants and for the collection of high-quality research data from funding for research design and analysis. These activities entail different skills, and rewarding the latter while marginalizing the former (11) will ensure further deterioration of our capacity and accelerate the offshoring of vital research.

• 2. Ensure that institutions are rewarded separately for these 2 functions in terms of recognition and academic acclaim as well as funding. Importantly, NIH funding is increasingly segregated into “haves” and “have-nots,” with the former characterized by the enormous basal infrastructures needed to compete in discovery science. If funding is allocated for site-based research, which does not require this infrastructure, the “have-nots” should be able to compete effectively for NIH funding within this system, thereby allowing the development of a group of committed sites, investigators, and study coordinators while also providing resources to build systems enabling recruitment, data collection, and quality assurance.

• 3. Develop networked coordinating centers devoted to the improvement of research across multiple sites, along with the design and analysis of multicenter trials. These centers should be required as a condition of funding to develop and sustain methods of collaboration with other coordinating centers and with site-based research organizations. This will necessitate an investment in technological tools, including those afforded by social networking, to encourage and foster these collaborations.

• 4. Participate vigorously with other NIH institutes to solve general administrative issues through the National Center to Advance Translational Science. The imperatives to address excessive delays in institutional review board review and contract approval, clarify billing issues and management of indirect costs, and develop common metrics for quality and efficiency in research are not disease specific, and common solutions customized to suit special needs will likely prove effective. This would entail working with U.S. Department of Health and Human Services to develop smoother collaboration among federal organizations and agencies, most particularly the Food and Drug Administration, which has regulatory oversight of industry-sponsored clinical research.

• 5. Incorporate clinical research within the learning health system, so that evidence generation becomes integral to the culture of clinical practice. This effort, which should be led by the NHLBI, would use electronic health records and registries as the primary substrates for data collection, significantly enhancing efficiency and reducing costs to systems burdened by redundant data systems and procedures. In addition to reducing reliance on clinical data reentry into research records, it should markedly reduce costly on-site monitoring visits, because data quality can be reviewed centrally using statistical outlier detection and process control.

This report by Kim et al. (1) represents a wake-up call. If we fail to heed it, we may see the U.S. clinical research enterprise go the way of so many other American industries: lost to more efficient overseas competitors. Such an outcome would be more than an economic disaster. It would also deprive the American public of relevant, high-quality evidence essential for making appropriate decisions about health care. But if we do succeed in an essential transformation of the clinical research system, we can renew a tradition of innovation and leadership while participating in critical global efforts to better understand the prevention and treatment cardiovascular disease around the world (12,13).

• American College of Cardiology Foundation